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(2) Patent Application Publication (10) Pub. No.: US 2009/0186834 A1 Talley Et Al

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(2) Patent Application Publication (10) Pub. No.: US 2009/0186834 A1 Talley Et Al US 20090.186834A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2009/0186834 A1 Talley et al. (43) Pub. Date: Jul. 23, 2009 (54) DIPHENYLEIETEROCYCLE CHOLESTEROL Publication Classification ABSORPTION INHIBITORS (51) Int. Cl. (75) Inventors: John Talley, Somerville, MA (US); 4. º,{} º Eduardo Martinez, St. Louis, MO ( .01) MA(US); (US); Daniel Regina Zimmer, Lundrigan, Somerville, # º5 (º .01) Charlestown, MA (US) A61 K. 3 1/675 (2006.01) s A61 K 31/415 (2006.01) Correspondence Address: C07D 233/00 (2006.01) HESLIN ROTHENBERG FARLEY & MESITI C07D 263/90 (2006.01) PC A61 K 31/42 (2006.01) 5 COLUMBIA. CIRCLE A61 K 31/40 (2006.01) C07D 207/00 (2006.01) (73) Assignee: MICROBIA, INC., Cambridge, A61R 31/397 (2006.01) MA (US) C07D 205/06) (2006.01) C07H I5/06) (2006.01) (21) Appl. No.: 11/909,482 (52) U.S. Cl. ........... 514/24: 548/186: 514/369: 548/119; 31, 21. 514/92; 514/94, 514/385; 548/316.4: 548/229; (22) PCT Filed: Mar. 24, 2006 514/376; 514/422; 514/424; 548/517: 548/541; (86) PCT No.: PCT/US2006/011197 514/210.01: 548/950, 536/4.1 § 371 (c)(1), (57) ABSTRACT (2), (4) Date: Dec. 12, 2008 Various azetidinone, pyrrolidine, imidazolidine, and oxazo - - - lidine derivatives are described, as are pharmaceutical com Related U.S. Application Data positions containing these compounds and methods of treat (60) Provisional application No. 60/664,863, filed on Mar. ment of diseases using these compounds. Other embodiments 24, 2005. are also described. US 2009/0186834 A1 Jul. 23, 2009 DIPEHENYLEHETEROCYCLE CHOLESTEROL [0004] In these compounds ABSORPTION INHIBITORS II FIELD OF THE INVENTION [0001] The invention relates to 1,4-diphenylazetidines, 1,4 diphenylazetidin-2-thiones, 1,4-diphenylthiazetidinediox ides, 1,5-diphenylpyrrolidin-2-ones, 1,5-diphenylimidazoli din-2-ones, 1,5-diphenyloxazolidin-2-ones, 1,5 diphenylpyrrolidin-2-thiones, 1,5-diphenylimidazolidin-2 thiones, and 1,5-diphenyloxazolidin-2-thiones useful for the treatment of hypercholesterolemia and other diseases and conditions. BACKGROUND OF THE INVENTION each independently represent an aryl or heteroaryl residue; Q is chosen from SO2 and C=S; U is (C2-C2)-alkylene in which one or more–CH2—may be [0002] 1,4-Diphenylazetidin-2-ones and their utility for replaced by a radical chosen from –S–, -SO)—, treating disorders of lipid metabolism are described in U.S. SO2—, -O-, -C(O)—, -CHOH-, -NH=, CHF, Pat. No. 6,498,156, U.S. Pat. No. RE37721, in US published CF2, —CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH patent applications 2004/0067913, 2004/0082561 and 2004/ (OSOAH)—, -CH(OPOAH,)—, -CH(OR”)—, or –CH 0.198700, in PCT applications WOO2/50027, WO2004/ (OSOAR”)—; R', Rº, Rº, Rt. Rº, and Rº, independently of 005247, WO2004/087655 and in European application EP 1 one another, are chosen from: 362 855, the disclosures of which are incorporated herein by H, F, Cl, Br, I, OH, CFs, NO, N, CN, COOH, COO(C. reference. An assessment of the activity of Y-lactams, fl-sul Cº)-alkyl, CONH2, CONH(C1-C4)-alkyl, CONIC, C2) tams, imidazolidinones, and oxazolidinones in inhibiting alkyl]2, (C1-C3-alkyl, (C2-Ca-alkenyl, (C2-Ca)-alkynyl, or cholesterol absorption was published by Dugaret al. [Bioorg. 0-(C1-C4)-alkyl, wherein the alkyl radical is unsubstituted or Med. Chem. Let. 5, 2947-2952 (1995)]. at least one hydrogen in the alkyl radical is replaced by fluorine; or C(=NH)(NH2), POAH, SOAH, SO2NH2, SO2NH(C1-C4)-alkyl, SO2NI(C, Co-alkyl]2, S-(d-Ca)-alkyl, SUMMARY OF THE INVENTION S—(CH2), phenyl, SO–(C, Ca)-all-yl, SO–(CH2), phe nyl, SO2–(Ci-Ca)-alkyl, or SO2–(CH2), phenyl, wherein n=0-6, and wherein the phenyl radical is unsubstituted or [0003] In a first aspect, the invention relates to compounds substituted one or two times, each substituent chosen inde of formula I or II pendently from: F, Cl, Br, I, OH, CFs, NO2, CN, OCFs, O—(C,Ca)-alkyl, (C,Ca)-alkyl, and NH2; and NH2, NH=(C, C2)-alkyl, N((C, CA)-alkyl). 2 NH(C-C2) acyl, phenyl, or O—(CH2), phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CFs, NO2, CN, OCFs, O-(C. C.) alkyl, (C, Ca)-alkyl, NH2.NH(C,Ca)-alkyl, N((C,Ca)-alkyl) 2, SO2CHA, COOH, COO–(C,CG)-alkyl, and CONH2; and R* may additionally be chosen from —OSO2–R” and —SO2–R' 10. R” represents one, two, three or four residues chosen inde HO pendently from H, halogen, -OH, loweralkyl, -O-lower alkyl, hydroxyloweralkyl, -CN, CFs, nitro, -SH, -S-low eralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, -PO3H2, II —SOAH, –B(OH)2, a sugar, a polyol, a glucuronide, a sugar carbam ate, –OSO2–R” and —SO2–R”; R” is chosen from H, halogen, -OH, loweralkyl, -O loweralkyl, methylenedioxy, ethylenedioxy, hydroxylower alkyl, -CN, CFs, nitro, -SH, -S-loweralkyl, amino, alky lamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, car boxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsul foxide, acylamino, amidino, -PO3H2, —SOs H, -B(OH)2. a sugar, a polyol, a glucuronide, a sugar carbamate, —OSO2–R” and —SO2–R”; and US 2009/0186834 A1 Jul. 23, 2009 R” is chosen from a sugar, a polyol, a glucuronide and a [0009] In a second aspect, the invention relates to pharma sugar carbamate. ceutical formulations comprising a pharmaceutically accept [0005] The invention also includes pharmaceutically able carrier and a compound of the invention having a phar acceptable salts of the foregoing and following compounds, maceutically acceptable counter anion and, optionally in any stereoisomeric form, or a mixture of any such com additionally comprising one or more of (1) a dyslipidemic pounds in any ratio. agent, (2) an anti-diabetic agent, (3) an anti-hypertensive [0006] The invention further relates to compounds of for agent, (4) an anti-obesity agent, (5) an agent used to treat mula III and IV: autoimmune disorders, (6) an agent used to treat demylena tion and its associated disorders, (7) an agent used to treat Alzheimer’s disease, (8) a blood modifier, (9) a hormone replacement agent/composition, (10) a chemotherapeutic III agent, (11) a peptide which mitigates one or more symptoms of atherosclerosis, (12) an anti-cancer agent, (13) an agent used to treat bone loss and associated disorders, (14) an inhibitor of cholesterol biosynthesis; (15) a cholesterol ester transfer protein (CETP) inhibitor; (16) a bile acid sequestrant; (17) a nicotinic acid or derivative thereof: (18) a peroxisome proliferator-activator receptor alpha agonist; (19) an acyl coenzyme A cholesterol acyltransferase (ACAT) inhibitor; (20) an obesity control medication; (21) a hypoglycemic agent; (22) an antioxidant, (23) an antihypertensive com IV pound and (24) other agents. [0010] In a third aspect, the invention relates to methods for preventing and/or treating a disorder of lipid metabolism, including hyperlipidemia, sitosterolemia and arteriosclerotic symptoms; inhibiting the absorption of cholesterol from the intestine; reducing the blood plasma or serum concentrations of LDL cholesterol; reducing the concentrations of choles terol and cholesterol ester in the blood plasma or serum; reducing blood plasma or serum concentrations of C-reactive protein (CRP), reducing blood plasma or serum concentra tions of triglycerides; reducing blood plasma or serum con centrations of apolipoprotein B; increasing blood plasma or wherein X is chosen from S and O: E is chosen from CH2, O, serum concentrations of high density lipoprotein (HDL) cho S and NR”; and Rºº is chosen from hydrogen and Ci to C, lesterol; increasing the fecal excretion of cholesterol; treating alkyl. The definitions of the remaining variables are as previ a clinical condition for which a cholesterol absorption inhibi ously described. Definitions are retained throughout this tor is indicated; reducing the incidence of cardiovascular document. disease-related events; reducing plasma or tissue concentra [0007] The invention further relates to compounds of for tion of at least one non-cholesterol sterol or 50-stanol; treat mula V: ing or preventing vascular inflammation; preventing, treating, orameliorating symptoms of Alzheimer’s Disease; regulating the production or level of at least one amyloid? peptide in the bloodstream and/or brain of a subject; regulating the amount of ApoR isoform 4 in the bloodstream and/or brain; prevent ing and/or treating obesity; reversing heart disease; reversing arterioslerotic plaque formation; and preventing or decreas ing the incidence of xanthomas. The methods comprise administering a compound described herein. [0011] Li a fourth aspect, the invention relates to methods and compositions for prevention or treatment of a cholesterol associated tumor. The methods comprise administering a therapeutically effective amount of a compound of the inven tion to a patient at risk of developing a cholesterol-associated tumor or already exhibiting a cholesterol-associated tumor. [0008] In these compounds R104a represents one, two, three The method also includes coadministering a therapeutically or four residues chosen independently from H, halogen, low effective amount of a compound of the invention and at least eralkyl, -O-loweralkyl, hydroxyloweralkyl, -CN, CFs, one other anticancer agent. nitro, -S-loweralkyl, amino, alkylamino, dialkylamino, [0012] The compounds and pharmaceutical formulations aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, described herein can also be used in methods for treating a alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, condition for which a cholesterol absorption inhibitor is indi carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, ami cated; preventing or treating a cholesterol related disease; dino, -PO3H2, —SO3H, -B(OH)2, a sugar, apolyol, a glu inhibiting the absorption of or reducing plasma or tissue curonide, a sugar carbamate, –SO,-R”, and –OSO2– concentration of one or more sterols or stanols; preventing or R} 10.
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